NM_017534.6:c.3263+15A>G

Variant names:

• chr17-10529321-T-C
• rs2277651
• NM_017534.6:c.3263+15A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017534.6(MYH2):​c.3263+15A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,611,590 control chromosomes in the GnomAD database, including 117,750 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10475 hom., cov: 32)
  • Exomes 𝑓: 0.37 (107275 hom.)
• Consequence: MYH2 NM_017534.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.149
• Publications: 8 publications found

Genes affected

MYH2 (HGNC:7572): (myosin heavy chain 2) Myosins are actin-based motor proteins that function in the generation of mechanical force in eukaryotic cells. Muscle myosins are heterohexamers composed of 2 myosin heavy chains and 2 pairs of nonidentical myosin light chains. This gene encodes a member of the class II or conventional myosin heavy chains, and functions in skeletal muscle contraction. This gene is found in a cluster of myosin heavy chain genes on chromosome 17. A mutation in this gene results in inclusion body myopathy-3. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Sep 2009]

MYHAS (HGNC:50609): (myosin heavy chain gene cluster antisense RNA) Predicted to enable primary miRNA binding activity. Predicted to be involved in response to muscle activity and skeletal muscle fiber development. Predicted to act upstream of or within with a positive effect on gene expression. Predicted to be located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-10529321-T-C is Benign according to our data. Variant chr17-10529321-T-C is described in ClinVar as Benign. ClinVar VariationId is 260822.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYH2	NM_017534.6	c.3263+15A>G		intron_variant	Intron 25 of 39	ENST00000245503.10	NP_060004.3
MYH2	NM_001100112.2	c.3263+15A>G		intron_variant	Intron 25 of 39		NP_001093582.1
MYHAS	NR_125367.1	n.168-38216T>C		intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYH2	ENST00000245503.10	c.3263+15A>G		intron_variant	Intron 25 of 39	1	NM_017534.6	ENSP00000245503.5

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53790 AN: 151816 Hom.: 10475 Cov.: 32

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.397

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.338

GnomAD2 exomes AF: 0.428 AC: 107256 AN: 250862 AF XY: 0.424

Gnomad AFR exome AF: 0.244

Gnomad AMR exome AF: 0.563

Gnomad ASJ exome AF: 0.368

Gnomad EAS exome AF: 0.826

Gnomad FIN exome AF: 0.392

Gnomad NFE exome AF: 0.347

Gnomad OTH exome AF: 0.386

GnomAD4 exome AF: 0.371 AC: 542186 AN: 1459656 Hom.: 107275 Cov.: 52 AF XY: 0.374 AC XY: 271603 AN XY: 726178

African (AFR) AF: 0.241 AC: 8071 AN: 33466

American (AMR) AF: 0.546 AC: 24417 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 9656 AN: 26134

East Asian (EAS) AF: 0.802 AC: 31846 AN: 39696

South Asian (SAS) AF: 0.484 AC: 41732 AN: 86252

European-Finnish (FIN) AF: 0.383 AC: 20303 AN: 53022

Middle Eastern (MID) AF: 0.398 AC: 2294 AN: 5766

European-Non Finnish (NFE) AF: 0.343 AC: 381212 AN: 1110282

Other (OTH) AF: 0.376 AC: 22655 AN: 60322

GnomAD4 genome AF: 0.354 AC: 53808 AN: 151934 Hom.: 10475 Cov.: 32 AF XY: 0.365 AC XY: 27092 AN XY: 74268

African (AFR) AF: 0.250 AC: 10363 AN: 41498

American (AMR) AF: 0.444 AC: 6785 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1277 AN: 3468

East Asian (EAS) AF: 0.805 AC: 4156 AN: 5164

South Asian (SAS) AF: 0.493 AC: 2377 AN: 4820

European-Finnish (FIN) AF: 0.397 AC: 4187 AN: 10540

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.346 AC: 23481 AN: 67840

Other (OTH) AF: 0.338 AC: 713 AN: 2110

Alfa AF: 0.349 Hom.: 2655

Bravo AF: 0.353

Asia WGS AF: 0.578 AC: 2007 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myopathy, proximal, and ophthalmoplegia Benign:4

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	8.6
DANN	Benign	0.77
PhyloP100		0.15
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2277651; hg19: chr17-10432638; COSMIC: COSV55432473;